G protein-coupled receptors (GPCRs) and their signaling pathways are the targets of many current therapeutics as well as drugs of abuse. Most currently used therapeutics were developed decades ago when few components of GPCR signaling systems were known. However, new therapeutics, such as agonists biased to evoke GPCR-arrestin signaling, are being developed as a consequence of identifying novel components and regulators of GPCR signaling networks. Such novel targets potentially enable long-standing problems associated with current therapeutics, such as drug tolerance, side effects or addiction, to be reduced or eliminated. This project addresses these long-term goals by identifying novel mechanisms that control GPCR signaling in the nervous system. It focuses on the R7 RGS family of G protein regulators, which have been shown genetically to be critical intracellular regulators of GPCR signaling throughout the nervous system, and which regulate the biological effects of opioids and amphetamines, and side effects of L-DOPA. The Aims will determine how R7 RGS proteins under the control of a palmitoylated allosteric regulator called R7BP (R7 RGS-binding protein) regulate the activity of adenylyl cyclases and cAMP signaling in neuronal cells. They will identify novel enzymes that regulate palmitate turnover on R7BP and establish the functions of these enzymes as regulators of GPCR signaling in neuronal cells. Lastly, they will determine whether global or local cycles of palmitate turnover regulate the intracellular trafficking and function of R7BP-bound R7 RGS complexes. New knowledge gained by this project will provide deeper understanding of neurobiological signaling processes controlled by R7 RGS proteins, new models for elucidating the functions of palmitate turnover in diverse aspects of cell signaling and disease, and new drug targets that potentially enhance the action or reduce the side effects of GPCR-targeted neurotherapeutics.